ontact: Sonja Mak
s.mak@update.europe.at
43-140-557-340
European College of Neuropsychopharmacology

Antidepressants in suicide prevention
Presented at the 21st Congress of the European College of Neuropsychopharmacology 2008, Barcelona, Spain

Antidepressants and suicide risk: what is the evidence?

In numerous short-term randomized clinical trials (RCTs) of antidepressants for depression in children and adolescents (<19 years), antidepressants are found to be associated with a slightly higher proportion (0.7%) of patients reporting suicidal ideation or a suicide attempt than control patients receiving placebo (Bridge et al., 2007). It is important to note that there are no completed suicides in these studies. Adults treated with SSRI antidepressants in randomized clinical trials have a similar risk of either non-fatal self harm or suicidal thoughts than those on placebo (Gunnell et al., 2005 & 2006). It is undisputable that at least among children and adolescents, antidepressants have some potential of causing harm to a small subgroup of vulnerable patients, at least in the beginning of treatment. However, there are several reasons why such trials are likely to create a distorted view of the total balance of benefits and harms of antidepressants:

First, short-term clinical trials are designed to produce statistical evidence of efficacy for regulatory purposes, and their duration is only as long as necessary to produce this evidence. Thus, the trial ends when the drug response has evolved. During the trial patients spend most of their weeks with possible side effects, but not yet full antidepressant response. With regard to suicidal behaviour, the benefits come with the response, gradually over time.

Second, for ethical reasons, subjects who are severely suicidal at the time of evaluation for the trial must be excluded, since they might receive placebo. This changes the balance between observed negative and positive effects with regard to suicidal behaviour in these trials. Worsening of mild pre-existing or newly emerging suicidal behaviour can be usually detected. However, as most severely suicidal patients must be excluded before a trial starts, it remains unknown whether they would benefit from the active treatment. As naturalistic studies do suggest such improvement, this bias is not merely hypothetical. Antidepressant trials have not been designed to investigate suicidal behaviour, and they cannot provide unbiased information on their overall effects related to it.

Third, factors resulting in short-term suicidal ideation, or even less severe suicide attempts do not necessarily result in significantly increased risk for completed suicide, as mental disorders and their symptoms related to completed suicides are usually more severe. There is no evidence of increased rates completed suicides in antidepressant trials (Khan et al, 2003).

Fourth, clinical trials do not reflect usual treatment. In usual care, the attending doctor can promptly discontinue antidepressants that involve intolerable side-effects, adjust dosage, and switch and combine agents. Antidepressants are only part of treatment, which should always include a trustful relationship between the doctor and the patient, with necessary support and psychosocial treatments.

The most important test for the role of antidepressants in suicide prevention is real life: In contrast to these randomized clinical trials, observational studies of antidepressant treatment, which typically include abundantly highly suicidal patients, demonstrate a marked alleviation of suicidal behaviour in the vast majority of patients. In clinical practice, the benefits of treatment are seen over time as the drug response consolidates. Patient population studies of adolescents report lower rates of suicide attempts and of adults both attempts and completions over time as treatment continues (Valuck et al., 2004; Jick et al., 2004; Simon et al., 2007; Sokero et al., 2006; Simon et al., 2006).

In many western countries (e.g. Korkeila et al., 2007), increasing use of antidepressants on the national and regional level expectedly correlates with declining suicide mortality. Of course, such ecological studies do not prove that antidepressants have caused the observed decline in suicides, but nevertheless, they are consistent with a positive or at worst, neutral net effect on suicides. Most importantly, there is no evidence for increased national suicide rates due to increased use of antidepressants.

Antidepressants reduce the severity, and the time a patient spends in a depressive state, which are credible factors in reducing the risk for suicidal acts.

Clinical implications

Depression is the most important single factor predisposing to suicide, and more than half of all subjects completing suicide are known to have suffered from depression. Thus, any treatment that is widely available, safe and efficacious in alleviating depression is plausible for purposes of suicide prevention.

Register-based and observational studies have provided individual-level information on depressed subjects on and off antidepressants in real life conditions: Compared to randomized clinical trials these studies give a more realistic account of risk of suicidal behaviour, and suggest antidepressants to be beneficial for suicide prevention.

While antidepressants likely have a potential for provoking suicidal behaviour in some vulnerable individuals in the early phases of treatment, from a public health perspective, the epidemiologically much more important effect of antidepressants is to alleviate depression and thus reduce the risk of suicide.